GNRH1

Summary

GNRH1 (gonadotropin releasing hormone 1, HGNC:4419) is a protein-coding gene on chromosome 8p21.2, encoding Progonadoliberin-1 (P01148). Stimulates the secretion of gonadotropins; it stimulates the secretion of both luteinizing and follicle-stimulating hormones.

This gene encodes a preproprotein that is proteolytically processed to generate a peptide that is a member of the gonadotropin-releasing hormone (GnRH) family of peptides. Alternative splicing results in multiple transcript variants, at least one of which is secreted and then cleaved to generate gonadoliberin-1 and GnRH-associated peptide 1. Gonadoliberin-1 stimulates the release of luteinizing and follicle stimulating hormones, which are important for reproduction. Mutations in this gene are associated with hypogonadotropic hypogonadism.

Source: NCBI Gene 2796 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypogonadotropic hypogonadism 12 with or without anosmia (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 10
• Clinical variants (ClinVar): 53 total — 2 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 48
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_001083111

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4419
Approved symbol	GNRH1
Name	gonadotropin releasing hormone 1
Location	8p21.2
Locus type	gene with protein product
Status	Approved
Aliases	LNRH
Ensembl gene	ENSG00000147437
Ensembl biotype	protein_coding
OMIM	152760
Entrez	2796

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000276414, ENST00000421054, ENST00000966630

RefSeq mRNA: 2 — MANE Select: NM_001083111 NM_000825, NM_001083111

CCDS: CCDS43725

Canonical transcript exons

ENST00000421054 — 4 exons

Exon	Start	End
ENSE00000980091	25421573	25421668
ENSE00001040669	25419258	25419460
ENSE00001598313	25424201	25424261
ENSE00001644930	25423190	25423331

Expression profiles

Bgee: expression breadth ubiquitous, 181 present calls, max score 86.95.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1261 / max 96.0755, expressed in 15 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
92404	0.1261	15

Top tissues by expression

282 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
tibial nerve	UBERON:0001323	86.95	gold quality
lower esophagus mucosa	UBERON:0035834	86.30	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.89	gold quality
cerebellar hemisphere	UBERON:0002245	80.89	gold quality
putamen	UBERON:0001874	80.81	gold quality
ascending aorta	UBERON:0001496	80.68	gold quality
cerebellar cortex	UBERON:0002129	80.63	gold quality
thoracic aorta	UBERON:0001515	80.48	gold quality
descending thoracic aorta	UBERON:0002345	80.48	gold quality
mucosa of transverse colon	UBERON:0004991	80.15	gold quality
right hemisphere of cerebellum	UBERON:0014890	79.96	gold quality
aorta	UBERON:0000947	79.29	gold quality
popliteal artery	UBERON:0002250	78.56	gold quality
tibial artery	UBERON:0007610	78.55	gold quality
skin of leg	UBERON:0001511	78.31	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	78.25	gold quality
lower esophagus	UBERON:0013473	78.13	gold quality
lower esophagus muscularis layer	UBERON:0035833	78.12	gold quality
skin of abdomen	UBERON:0001416	78.01	gold quality
left coronary artery	UBERON:0001626	77.83	gold quality
right coronary artery	UBERON:0001625	77.71	gold quality
left ovary	UBERON:0002119	77.64	gold quality
right uterine tube	UBERON:0001302	77.53	gold quality
cerebellum	UBERON:0002037	77.53	gold quality
apex of heart	UBERON:0002098	77.45	gold quality
endocervix	UBERON:0000458	77.42	gold quality
granulocyte	CL:0000094	77.34	gold quality
sural nerve	UBERON:0015488	77.21	gold quality
muscle layer of sigmoid colon	UBERON:0035805	76.93	gold quality
coronary artery	UBERON:0001621	76.81	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.39

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
EGR1	Activation

Upstream regulators (CollecTRI, top): AHR, AR, ARNT, CREB1, DLX1, DLX2, EGR1, ESR1, ESR2, FOS, GATA4, GATA5, HESX1, IRF2BPL, JUN, MEF2A, MSX1, MSX2, NCOA3, NF1, NR5A1, OTX2, PGR, PITX1, PITX2, POU1F1, POU2F1, POU2F2, POU3F1, POU3F2, PURB, RARA, SP1, SP3, STAT5B, TFAP2A, TTF1

miRNA regulators (miRDB)

10 targeting GNRH1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-383-3P	99.85	65.84	1359
HSA-MIR-891B	99.59	69.81	1083
HSA-MIR-4506	99.34	67.47	526
HSA-MIR-7151-3P	99.04	69.72	2370
HSA-MIR-6512-5P	98.76	69.29	1195
HSA-MIR-455-5P	98.74	67.31	795
HSA-MIR-1237-3P	98.55	67.65	1423
HSA-MIR-541-5P	98.24	67.77	1181

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• data indicate that the promoter region between -992 and -795 contains elements both essential and sufficient for targeting gene expression to GnRH neurons (PMID:11875100)
• Coupling of GnRH concentration and the GnRH receptor-activated gene program (PMID:12040003)
• JunD activated by LHRH acts as a modulator of cell proliferation and cooperates with the anti-apoptotic and anti-mitogenic functions of LHRH. (PMID:12054733)
• GnRH-II and GnRH-I interact directly with T cells and trigger gene transcription, adhesion, chemotaxis and homing to specific organs, which may be of clinical relevance. (PMID:12447356)
• regulation of GnRH-I and GnRH-II gene expression in the ovary (PMID:12770744)
• Genetic analysis has excluded sequence variations in GNRH1 and GNRHR in four families with recessive IHH, suggesting the existence of a novel, as-yet-undiscovered gene for this condition. (PMID:12788881)
• gonadotropin releasing hormone-II is more effective than gonadotropin releasing hormone-I in stimulating leptin secretion (PMID:12969578)
• Neurons respond to GnRH with time- and dose-dependent increases in GnRH gene expression and protein release. (PMID:14565958)
• Review. The proliferation of human ovarian cancer cell lines is time- and dose-dependently reduced by GnRH and its superagonistic analogs. (PMID:14594454)
• Experimental evidence indicates that GnRH-I is expressed, together with its receptors, in tumors of the reproductive tract. Activation of type I GnRH receptors consistently decreases cell proliferation, mainly by interfering with growth factors. (PMID:14726258)
• GnRH I and GnRH II have both common and discrete cellular distributions in the placenta and decidua and suggest that these two hormones are capable of eliciting their biological actions in an autocrine and/or paracrine manner (PMID:15001648)
• In placental cytotrophoblasts, the upstream transcription start site of GnRH gene was the major one and gave rise to an mRNA level three times higher than the downstream start site. Estradiol downregulated GnRH gene expression in a dose-dependent fashion. (PMID:15062568)
• expression of the GnRH gene is regulated in neurons by TALE homeodomain proteins and Oct-1 (PMID:15138251)
• It is suggested that during the early to midfollicular phase the ovaries produce a gonadotrophin surge attenuating factor that antagonizes the pituitary-sensitizing effect of E2 to GnRH. (Gonadotrophin surge attenuating factor) (PMID:15229199)
• These galanin-LHRH and LHRH-galanin contacts may be functional synapses, and they may be the morphological substrate of the galanin-controlled gonadal functions in humans. (PMID:15283968)
• Genetic variation in GNRH1 is not likely to be a substantial modulator of pubertal timing in the general population. (PMID:15546906)
• Progesterone receptor isoform p4 is a potent regulator of GnRHRI at the transcriptional level as well as GnRH I mRNA. (PMID:15562029)
• GnRH-I induced greater proliferation in normal B-cells than IL-2 treatment alone. (PMID:15578334)
• GnRH may protect ovarian cancer cells from stimulated apoptotic cell death. (PMID:15809743)
• LHRH receptors are expressed in human RCC specimens (PMID:16061872)
• analysis of gonadotropin-releasing hormone ligand conformation and receptor selectivity (PMID:16157590)
• GnRH1 gene is not responsible for idiopathic hypogonadotropic hypogonadism, at least as mutations are concerned (PMID:16359986)
• we observed that LHRH-(1-5), the specific processed peptide of LHRH-I, upregulates LHRH-II mRNA expression in Ishikawa cells, an endometrial cell line but does not exert any influence on LHRH-I mRNA levels (PMID:17202595)
• estrogens may exert direct actions upon GnRH neurons exclusively through ER-beta (PMID:17456575)
• Our data indicate a bridging interaction between Arg500 of the N-domain and Arg8 of GnRH that involves a chloride ion may account for its role in the specificity of the N-domain for endoproteolytic cleavage of the substrate at the NH2-terminus in vitro (PMID:17605472)
• Data show that GnRH neurones morphologically interact with astrocytes and tanycytes in the human brain and suggest that glial cells may contribute to the process by which the neuroendocrine brain controls the function of GnRH neurones in humans. (PMID:17680884)
• 12% of Kallman syndrome males have KAL1 deletions, but intragenic deletions of the FGFR1, GNRH1, GNRHR, GPR54 and NELF genes are uncommon in Idiopathic hypogonadotropic hypogonadism/Kallman syndrome. (PMID:18463157)
• analysis of how GNRH I and GNRH II inhibit cell growth (PMID:18467526)
• GnRH-I and -II induce apoptosis in human granulosa cells through GnRH-I receptors, which mediate the proteolytic caspase cascade involving caspase-8 (the initiator) and caspase-3 and -7 (the effectors). (PMID:18477660)
• REVIEW: role of GnRH in the control of tumor growth, progression, and dissemination (PMID:18959738)
• summarize the current understanding of the antiproliferative actions of GnRH analogs, as well as the recent observations of GnRH effects on ovarian cancer cell apoptosis and motogenesis,and the molecular mechanisms that mediate GnRH actions (PMID:18959739)
• Data show that over half of meningiomas may be regulated by GnRH-GnRH-R expression in an autocrine fashion. (PMID:18980792)
• the antitumor effect of gonadotropin-releasing hormone type i is mediated by the activation of type I (but not of type II) GnRH-R (PMID:19190109)
• identified a homozygous GNRH1 frameshift mutation in the sequence encoding the N-terminal region of the signal peptide-containing prepro-GnRH in a teenage brother & sister who had normosmic idiopathic hypogonadotropic hypogonadism (PMID:19535795)
• GNRH1 mutations are a genetic cause of idiopathic hypogonadotropic hypogonadism. (PMID:19567835)
• Common variants of the GNRH1 and GNRHR genes are not associated with risk of invasive breast cancer in Caucasians (PMID:19640273)
• GNRH1 is mutated in people with familial hypogonadotropic hypogonadism. (PMID:19849976)
• cadherin switching and p120(ctn) signaling as important targets of GnRH function and as novel mediators of invasiveness and tumor progression in ovarian cancer. (PMID:20118984)
• Metabolic signals are integrated at the levels of first-order neurons equipped with the proper receptors, ant that these neurons send their signals towards hypothalamic GnRH neurons which constitute the integrative element of this network. (PMID:20138117)
• The major genes associated with GnRH-dependent pubertal disorders, are reviewed. (PMID:20188792)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	gnrh3	ENSDARG00000056214
mus_musculus	Gnrh1	ENSMUSG00000015812
rattus_norvegicus	Gnrh1	ENSRNOG00000066847

Paralogs (1): GNRH2 (ENSG00000125787)

Protein

Protein identifiers

Progonadoliberin-1 — P01148 (reviewed: P01148)

Alternative names: Progonadoliberin I

All UniProt accessions (1): P01148

UniProt curated annotations — full annotation on UniProt →

Function. Stimulates the secretion of gonadotropins; it stimulates the secretion of both luteinizing and follicle-stimulating hormones.

Subcellular location. Secreted.

Post-translational modifications. The precursor is cleaved by ACE, which removes the Gly-Lys-Arg peptide at the C-terminus, leading to mature hormone. The mature form of Gonadoliberin-1 is also cleaved and degraded by ACE.

Disease relevance. Hypogonadotropic hypogonadism 12 with or without anosmia (HH12) [MIM:614841] A disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. In some cases, it is associated with non-reproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss. Anosmia or hyposmia is related to the absence or hypoplasia of the olfactory bulbs and tracts. Hypogonadism is due to deficiency in gonadotropin-releasing hormone and probably results from a failure of embryonic migration of gonadotropin-releasing hormone-synthesizing neurons. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism is referred to as Kallmann syndrome, whereas in the presence of a normal sense of smell, it has been termed normosmic idiopathic hypogonadotropic hypogonadism (nIHH). The disease is caused by variants affecting distinct genetic loci, including the gene represented in this entry. The genetics of hypogonadotropic hypogonadism involves various modes of transmission. Oligogenic inheritance has been reported in some patients carrying mutations in GNRH1 as well as in other HH-associated genes including PROKR2 and FGFR1.

Miscellaneous. The 3D-structure was determined for the synthetic analog Triptorelin.

Similarity. Belongs to the GnRH family.

RefSeq proteins (2): NP_000816, NP_001076580* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002012	GnRH	Conserved_site
IPR004079	Gonadoliberin_I_precursor	Family
IPR019792	Gonadoliberin	Family

Pfam: PF00446

UniProt features (14 total): site 5, modified residue 2, sequence variant 2, peptide 2, signal peptide 1, chain 1, helix 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
4D5M	X-RAY DIFFRACTION	0.85
9U4W	ELECTRON MICROSCOPY	3.18

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P01148-F1	71.63	0.11

Antibody-complex structures (SAbDab): 1 — 9U4W

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (5): 26–27 (cleavage; by ace); 26 (appears to be essential for biological activity); 28–29 (cleavage; by ace); 30–31 (cleavage; by ace); 33–34 (cleavage; by ace)

Post-translational modifications (2): 33, 24

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-375281	Hormone ligand-binding receptors
R-HSA-416476	G alpha (q) signalling events

MSigDB gene sets: 270 (showing top): BROWNE_HCMV_INFECTION_30MIN_DN, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_RESPONSE_TO_ETHANOL, GOBP_RESPONSE_TO_PROSTAGLANDIN_E, GOBP_NEGATIVE_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_MALE_SEX_DETERMINATION, GOBP_SEX_DETERMINATION, GOBP_RESPONSE_TO_POTASSIUM_ION, GOBP_NEGATIVE_REGULATION_OF_CELL_CELL_ADHESION, GOBP_NEUROGENESIS, GOBP_CELL_CELL_SIGNALING, GOBP_RESPONSE_TO_METAL_ION, GOBP_CELL_CELL_ADHESION

GO Biological Process (21): signal transduction (GO:0007165), cell-cell signaling (GO:0007267), female pregnancy (GO:0007565), regulation of gene expression (GO:0010468), regulation of signaling (GO:0023051), male sex determination (GO:0030238), response to lipopolysaccharide (GO:0032496), negative regulation of immature T cell proliferation (GO:0033087), response to testosterone (GO:0033574), response to prostaglandin E (GO:0034695), response to potassium ion (GO:0035864), negative regulation of apoptotic process (GO:0043066), estrous cycle (GO:0044849), response to ethanol (GO:0045471), response to steroid hormone (GO:0048545), response to prolactin (GO:1990637), regulation of ovarian follicle development (GO:2000354), negative regulation of neuron migration (GO:2001223), multicellular organism development (GO:0007275), ovulation cycle (GO:0042698), response to peptide hormone (GO:0043434)

GO Molecular Function (3): hormone activity (GO:0005179), gonadotropin hormone-releasing hormone activity (GO:0005183), gonadotropin-releasing hormone receptor binding (GO:0031530)

GO Cellular Component (8): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), Golgi-associated vesicle (GO:0005798), dendrite (GO:0030425), perikaryon (GO:0043204), axon terminus (GO:0043679), cytoplasmic side of rough endoplasmic reticulum membrane (GO:0098556), neurosecretory vesicle (GO:1990008)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Class A/1 (Rhodopsin-like receptors)	1
GPCR downstream signalling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
signaling	3
response to lipid	3
cell communication	2
response to ketone	2
response to alcohol	2
cellular anatomical structure	2
cellular process	1
regulation of cellular process	1
cellular response to stimulus	1
multi-organism reproductive process	1
multi-multicellular organism process	1
gene expression	1
regulation of macromolecule biosynthetic process	1
regulation of biological process	1
multicellular organism development	1
sex determination	1
response to molecule of bacterial origin	1
response to oxygen-containing compound	1
immature T cell proliferation	1
regulation of immature T cell proliferation	1
negative regulation of T cell proliferation	1
response to prostaglandin	1
response to metal ion	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
ovulation cycle	1
response to hormone	1
response to peptide hormone	1
ovarian follicle development	1
regulation of developmental process	1
neuron migration	1
negative regulation of cell migration	1
regulation of neuron migration	1
multicellular organismal process	1
anatomical structure development	1
rhythmic process	1
multicellular organismal reproductive process	1
receptor ligand activity	1
hormone activity	1

Protein interactions and networks

STRING

1766 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GNRH1	GNRHR	P30968	999
GNRH1	GNRH2	O43555	981
GNRH1	KISS1R	Q969F8	969
GNRH1	KISS1	Q15726	967
GNRH1	AMH	P03971	918
GNRH1	TAC3	Q9UHF0	909
GNRH1	TACR3	P29371	905
GNRH1	FSHB	P01225	903
GNRH1	PROK2	Q9HC23	897
GNRH1	PRL	P01236	896
GNRH1	TRH	P20396	893
GNRH1	ANOS1	P23352	880
GNRH1	PROKR2	Q8NFJ6	878
GNRH1	POMC	P01189	867
GNRH1	GHRH	P01286	858

IntAct

3 interactions, top by confidence:

A	B	Type	Score
GNRH1	TRIM68	psi-mi:“MI:0914”(association)	0.530
GNRH1	EMC8	psi-mi:“MI:0914”(association)	0.350

BioGRID (10): MTX1 (Affinity Capture-MS), TRIM68 (Affinity Capture-MS), MALSU1 (Affinity Capture-MS), EMC8 (Affinity Capture-MS), EMC3 (Affinity Capture-MS), EMC4 (Affinity Capture-MS), HSPA5 (Affinity Capture-MS), GNRH1 (Biochemical Activity), MALSU1 (Affinity Capture-MS), TRIM68 (Affinity Capture-MS)

ESM2 similar proteins: A8MXK1, O09163, O46633, O54713, O76096, O95684, P01148, P01268, P01269, P01270, P01344, P04089, P07352, P07456, P07490, P10286, P10764, P13562, P14745, P15696, P17647, P23695, P33717, P37042, P41694, P49921, P51459, P51462, P52212, P55247, Q05078, Q08279, Q27IM2, Q28588, Q29423, Q2YDD1, Q3SXP7, Q4R7M4, Q4R7V3, Q5GAN6

Diamond homologs: O09163, O54713, O73812, P01148, P07490, P13562, P37042, P45656, P49921, P51918, P51919, P55247, P70074, Q28588, Q8UW80, Q90Y63, Q95335, Q9IA10, Q9IAU2, P33439, P51917, P51925, Q8UW81, Q9DG36, Q9DGC8, P51922, Q8UW82, Q9IA09, P30973, P45652, P51921, P51923, Q9DD49, O43555, O73811, P37044, P43306, P45653, P69107, P69108

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
POU3F2	“up-regulates quantity by expression”	GNRH1	“transcriptional regulation”
triptorelin	“up-regulates activity”	GNRH1	“chemical activation”
GNRH1	“down-regulates activity”	AR	binding
IRF2BPL	“up-regulates quantity by expression”	GNRH1	“transcriptional regulation”
GNRH1	“up-regulates quantity by expression”	EGR1	“transcriptional regulation”
GNRH1	“up-regulates activity”	EGR1	binding
PITX1	“down-regulates quantity by repression”	GNRH1	“transcriptional regulation”
PITX2	“down-regulates quantity by repression”	GNRH1	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

53 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	1
Uncertain significance	24
Likely benign	9
Benign	7

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
1388091	NM_001083111.2(GNRH1):c.60dup (p.Cys21fs)	Pathogenic
14417	NM_001083111.2(GNRH1):c.18dup (p.Leu7fs)	Pathogenic
156555	NM_001083111.2(GNRH1):c.87del (p.Leu30fs)	Likely pathogenic

SpliceAI

240 predictions. Top by Δscore:

Variant	Effect	Δscore
8:25421567:ACTT:A	donor_loss	1.0000
8:25421568:CTTA:C	donor_loss	1.0000
8:25421570:TACCA:T	donor_loss	1.0000
8:25421571:A:AC	donor_gain	1.0000
8:25421572:C:CC	donor_gain	1.0000
8:25421665:CTAT:C	acceptor_gain	1.0000
8:25421666:TAT:T	acceptor_gain	1.0000
8:25421668:TCTGA:T	acceptor_loss	1.0000
8:25421669:C:CC	acceptor_gain	1.0000
8:25421669:C:CG	acceptor_loss	1.0000
8:25421670:T:A	acceptor_loss	1.0000
8:25423185:CTTA:C	donor_loss	1.0000
8:25423186:TTACC:T	donor_loss	1.0000
8:25423187:TA:T	donor_loss	1.0000
8:25423189:CCT:C	donor_gain	1.0000
8:25423328:CATT:C	acceptor_gain	1.0000
8:25423330:TT:T	acceptor_gain	1.0000
8:25423331:TC:T	acceptor_loss	1.0000
8:25423332:C:CA	acceptor_loss	1.0000
8:25423332:C:CC	acceptor_gain	1.0000
8:25419456:CTTTC:C	acceptor_gain	0.9900
8:25419457:TTTC:T	acceptor_gain	0.9900
8:25419460:CCTGA:C	acceptor_loss	0.9900
8:25419461:C:CA	acceptor_loss	0.9900
8:25419462:T:C	acceptor_loss	0.9900
8:25421571:AC:A	donor_gain	0.9900
8:25421572:CC:C	donor_gain	0.9900
8:25421572:CCA:C	donor_gain	0.9900
8:25421572:CCAG:C	donor_gain	0.9900
8:25421572:CCAGA:C	donor_gain	0.9900

AlphaMissense

587 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:25423253:C:A	W26C	0.955
8:25423253:C:G	W26C	0.955
8:25423226:C:A	K35N	0.939
8:25423226:C:G	K35N	0.939
8:25423223:T:A	R36S	0.935
8:25423223:T:G	R36S	0.935
8:25423255:A:G	W26R	0.931
8:25423255:A:T	W26R	0.931
8:25423227:T:G	K35T	0.890
8:25423252:A:G	S27P	0.877
8:25423256:G:C	H25Q	0.877
8:25423256:G:T	H25Q	0.877
8:25423233:C:A	G33V	0.857
8:25423233:C:T	G33E	0.856
8:25423251:G:A	S27F	0.854
8:25423259:C:A	Q24H	0.854
8:25423259:C:G	Q24H	0.854
8:25423230:C:A	G34V	0.848
8:25423258:G:C	H25D	0.844
8:25423236:G:T	P32H	0.818
8:25423237:G:A	P32S	0.810
8:25423242:A:G	L30P	0.804
8:25423224:C:G	R36T	0.801
8:25423224:C:A	R36I	0.792
8:25423254:C:G	W26S	0.782
8:25423227:T:A	K35M	0.781
8:25423230:C:T	G34E	0.778
8:25423234:C:G	G33R	0.774
8:25423234:C:T	G33R	0.774
8:25423228:T:C	K35E	0.771

dbSNP variants (sampled 300 via entrez): RS1000033406 (8:25420720 C>CA), RS1000919080 (8:25425518 TA>T,TAA), RS1001044226 (8:25419230 T>C,G), RS1001095213 (8:25418871 C>A,G), RS1001226325 (8:25424988 G>A), RS1002082356 (8:25425888 T>C), RS1002204709 (8:25420020 C>T), RS1002920367 (8:25422334 C>CCCAG), RS1003952734 (8:25426501 G>C), RS1004042830 (8:25419749 G>C), RS1004067400 (8:25427012 A>C,G), RS1004129865 (8:25420153 T>C), RS1004147686 (8:25426277 T>A,C), RS1004325655 (8:25420066 G>A), RS1004497960 (8:25426502 C>T)

Disease associations

OMIM: gene MIM:152760 | disease phenotypes: MIM:227200, MIM:614841, MIM:147950

GenCC curated gene-disease

Disease	Classification	Inheritance
hypogonadotropic hypogonadism 12 with or without anosmia	Strong	Autosomal recessive
hypogonadotropic hypogonadism	Supportive	Autosomal dominant

Mondo (3): amenorrhea (MONDO:0001836), hypogonadotropic hypogonadism 12 with or without anosmia (MONDO:0013914), hypogonadotropic hypogonadism (MONDO:0018555)

Orphanet (1): Normosmic congenital hypogonadotropic hypogonadism (Orphanet:432)

HPO phenotypes

48 total (30 of 48 shown, HPO-id order):

HPO	Term
HP:0000002	Abnormality of body height
HP:0000007	Autosomal recessive inheritance
HP:0000013	Hypoplasia of the uterus
HP:0000026	Male hypogonadism
HP:0000027	Azoospermia
HP:0000028	Cryptorchidism
HP:0000044	Hypogonadotropic hypogonadism
HP:0000054	Micropenis
HP:0000118	Phenotypic abnormality
HP:0000134	Female hypogonadism
HP:0000164	Abnormality of the dentition
HP:0000175	Cleft palate
HP:0000316	Hypertelorism
HP:0000458	Anosmia
HP:0000716	Depression
HP:0000739	Anxiety
HP:0000771	Gynecomastia
HP:0000786	Primary amenorrhea
HP:0000789	Infertility
HP:0000802	Impotence
HP:0000823	Delayed puberty
HP:0000869	Secondary amenorrhea
HP:0000938	Osteopenia
HP:0000939	Osteoporosis
HP:0001608	Abnormality of the voice
HP:0002215	Sparse axillary hair
HP:0002225	Sparse pubic hair
HP:0002231	Sparse body hair
HP:0002555	Absent pubic hair
HP:0002750	Delayed skeletal maturation

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST005863_13	Menopause (age at onset)	3.000000e-13
GCST005863_26	Menopause (age at onset)	4.000000e-12
GCST006958_3	Length of menstrual cycle	1.000000e-10
GCST006979_454	Heel bone mineral density	2.000000e-15
GCST009391_327	Metabolite levels	7.000000e-06
GCST90002385_161	High light scatter reticulocyte count	1.000000e-15
GCST90002386_472	High light scatter reticulocyte percentage of red cells	7.000000e-16
GCST90002387_392	Immature fraction of reticulocytes	3.000000e-12
GCST90002405_499	Reticulocyte count	7.000000e-12
GCST90002406_269	Reticulocyte fraction of red cells	2.000000e-12

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004704	age at menopause
EFO:0009270	heel bone mineral density
EFO:0010432	triacylglycerol 56:5 measurement
EFO:0007986	reticulocyte count

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D000568	Amenorrhea	C23.550.568.500
C535764	Eunuchoidism, familial hypogonadotropic (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

35 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Estradiol	decreases reaction, increases reaction, increases secretion, decreases expression, affects cotreatment	3
Progesterone	decreases abundance, affects cotreatment, increases secretion, decreases reaction	2
Tamoxifen	decreases reaction, increases secretion, affects cotreatment	2
Valproic Acid	decreases expression	2
GSK-J4	increases expression	1
aminomethylphosphonic acid (AMPA)	increases expression	1
bisphenol A	decreases expression	1
carvone	increases expression, increases secretion	1
tris(2-butoxyethyl) phosphate	affects expression	1
ochratoxin A	increases expression	1
potassium chromate(VI)	affects cotreatment, increases expression	1
testosterone-3-carboxymethyloxime-bovine serum albumin conjugate	affects expression	1
epigallocatechin gallate	increases expression, affects cotreatment	1
di-n-butylphosphoric acid	affects expression	1
bifenthrin	increases expression	1
acyline	decreases activity	1
bisphenol S	affects expression	1
jinfukang	decreases expression	1
Sevoflurane	increases expression	1
Glyphosate	increases expression	1
Atrazine	increases expression	1
Hexachlorocyclohexane	affects cotreatment, increases expression	1
Cisplatin	decreases expression	1
Clomiphene	decreases reaction, increases reaction, increases secretion	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
DDT	affects cotreatment, increases expression	1
Hydrogen Peroxide	affects expression	1
Lipopolysaccharides	increases expression, increases reaction	1
Melitten	increases response to substance, affects binding	1
Mercury	increases expression	1

Clinical trials (associated diseases)

111 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00328926	PHASE4	TERMINATED	Luveris® (Lutropin Alfa for Injection) in Women With Hypogonadotropic Hypogonadism (Luteinizing Hormone [LH] Less Than [<] 1.2 International Unit Per Liter [IU/L])
NCT01403532	PHASE4	COMPLETED	Sequential Therapy for Hypogonadotropic Hypogonadism
NCT01454011	PHASE4	COMPLETED	The Effect of Testosterone Replacement on the High Density Lipoprotein Cholesterol Subgroups
NCT01601327	PHASE4	COMPLETED	Effects of Medications in Patients With Hypogonadism
NCT02310074	PHASE4	UNKNOWN	Efficacy and Safety of Pulsatile Gonadotropin Releasing Hormone Pump Treatment in Patients With Idiopathic Hypogonadotropic Hypogonadism
NCT02880280	PHASE4	UNKNOWN	Human Menopausal Gonadotropin Combining With Human Chorionic Gonadotropin Treat Congenital Hypogonadotropic Hypogonadism
NCT03490513	PHASE4	COMPLETED	Aromatase Inhibitors and Weight Loss in Severely Obese Men With Hypogonadism
NCT04456296	PHASE4	COMPLETED	A Study of the Effect of Testosterone Replacement Therapy on Blood Pressure in Adult Male Participants With Hypogonadism
NCT05205837	PHASE4	TERMINATED	A Randomized, Double-blinded, Clinical, Placebo-controlled Trial on the Effects of Therapy With Letrozole and hUman Choriongonadotropin in Male Hypogonadism Induced by Illicit Use of Anabolic Androgenic Steroids- The LUCAS Trial
NCT01103518	PHASE4	UNKNOWN	Ethinyl Estradiol and Cyproterone Acetate in Irregular Menstruation
NCT01206153	PHASE4	COMPLETED	Metformin for Treatment Antipsychotic Induced Amenorrhea in Female Schizophrenic Patients
NCT02393482	PHASE4	UNKNOWN	Psychological Impact of Amenorrhea in Women With Endometriosis
NCT00467870	PHASE3	COMPLETED	Long-term Safety Study of Intramuscular Injections of 750 mg and 1000 mg Testosterone Undecanoate in Hypogonadal Men
NCT00962637	PHASE3	COMPLETED	Study to Evaluate the Safety and Efficacy of Androxal™ Treatment in Men With Secondary Hypogonadism
NCT01067365	PHASE3	COMPLETED	Study to Evaluate the Safety and Efficacy of Androxal Treatment in Men With Secondary Hypogonadism
NCT01532414	PHASE3	COMPLETED	Phase III Study to Evaluated Morning Testosterone Normalization in Men With Secondary Hypogonadism
NCT01534208	PHASE3	COMPLETED	Safety Study of Enclomiphene Citrate in the Treatment of Men With Secondary Hypogonadism
NCT01709331	PHASE3	COMPLETED	A Study of the Efficacy and Safety of Corifollitropin Alfa (MK-8962) in Combination With Human Chorionic Gonadotropin (hCG) in Adult Men With Hypogonadotropic Hypogonadism (HH) (P07937)
NCT01739582	PHASE3	COMPLETED	An Extension Study of Enclomiphene Citrate in the Treatment of Men With Secondary Hypogonadism
NCT01739595	PHASE3	COMPLETED	Phase III Study to Evaluate Morning Testosterone Normalization in Overweight Men With Secondary Hypogonadism
NCT01993212	PHASE3	COMPLETED	A Randomized, Double Blind, Placebo-Controlled, Multi-Center Phase III Study in Men With Acquired Hypogonadotropic Hypogonadism to Compare Changes in Testosterone and Sperm Concentration Following Treatment With 12.5 mg or 25 mg Androxal or AndroGel 1.62%
NCT01993225	PHASE3	COMPLETED	A Randomized, Double Blind, Placebo-Controlled, Multi-Center Phase III Study in Men With Acquired Hypogonadotropic Hypogonadism to Compare Changes in Testosterone and Sperm Concentration Following Treatment With 12.5 mg or 25 mg Androxal or AndroGel 1.62%
NCT02110368	PHASE3	COMPLETED	Bioequivalence Study of Test and Reference Testosterone Topical Gel, 1.62% Metered Pump in Testosterone Deficient Adult Male Subjects Under Fasting Conditions
NCT03019575	PHASE3	COMPLETED	Efficacy and Safety of Corifollitropin Alfa (MK-8962) in Combination With Human Chorionic Gonadotropin (hCG) in Adolescent Males With Hypogonadotropic Hypogonadism (HH) (MK-8962-043)
NCT06561594	PHASE3	NOT_YET_RECRUITING	To Evaluate Recombinant Human Follicle Stimulating Hormone-CTP Fusion Protein Injection or Placebo Combined With Chorionic Gonadotropin for Injection
NCT00827151	PHASE3	WITHDRAWN	Bone Mass Accrual in Adolescent Athletes
NCT00193661	PHASE2	COMPLETED	Observation Study of T-Gel (1%) in Treatment of Adolescent Boys With Hypogonadism
NCT00383656	PHASE2	UNKNOWN	Pulsatile GnRH in Anovulatory Infertility
NCT00697814	PHASE2	COMPLETED	Clomiphene in Males With Prolactinomas and Persistent Hypogonadism
NCT00706719	PHASE2	COMPLETED	To Evaluate Sperm Parameters in Men With Secondary Hypogonadism Previously Treated With Topical Testosterone
NCT00911586	PHASE2	COMPLETED	Pharmacokinetic Study to Determine Time to Steady-state
NCT01155518	PHASE2	TERMINATED	Hypogonadism in Young Men With Type 2 Diabetes
NCT01191320	PHASE2	COMPLETED	Study to Evaluate the Efficacy of Androxal in Controlling Blood Glucose in Men With Type-2 Diabetes Mellitus
NCT01270841	PHASE2	COMPLETED	Normalization of Morning Testosterone Levels in Men With Secondary Hypogonadism
NCT01386606	PHASE2	COMPLETED	The Effect on Androxal Versus Androgel on Morning Testosterone in Men With Secondary Hypogonadism (Low Testosterone)
NCT01894308	PHASE2	NOT_YET_RECRUITING	A Dose Ranging Study to Examine TDS-Testosterone 5%
NCT02369796	PHASE2	TERMINATED	A Phase 2a Pharmacodynamic Study of TAK-448 in Participants With Hypogonadotropic Hypogonadism
NCT02443090	PHASE2	UNKNOWN	Safety and Efficacy Study of Oral Fispemifene for the Treatment of Sexual Dysfunction in Hypogonadal Men
NCT02651688	PHASE2	COMPLETED	A Multi-Center Study in Men With Acquired Hypogonadotropic Hypogonadism to Compare Changes in Body Composition and Metabolic Parameters With Diet and Exercise in Conjunction With Treatment With 12.5 mg or 25 mg Enclomiphene
NCT02730169	PHASE2	COMPLETED	Safety and Efficacy of BGS649 in Male Obese Subjects With Hypogonadotropic Hypogonadism